1. Field of the Invention
The present invention relates to compositions and methods for treating wasting. More specifically, the present invention relates to treatments for increasing muscle mass in individuals with chronic obstructive pulmonary disease. The present invention also relates to the use of a composition comprising clomiphene enriched for trans-clomiphene reagents for treating hypogonadism, preferably secondary hypogonadism, in individuals with chronic obstructive pulmonary disease.
2. Description of Related Art
a. Testosterone
Testosterone is the primary male androgen, playing a vital role in overall male health. Testosterone is essential to the development and maintenance of specific reproductive tissues (testes, prostate, epididymis, seminal vesicle and penis) and male secondary sex characteristics. It plays a key role in libido and erectile function and is necessary for the initiation and maintenance of spermatogenesis. Testosterone also has important functions not related to reproductive tissues. For example, it positively affects body composition by increasing nitrogen retention, which supports lean body mass, muscle size and strength. It also acts on bone to stimulate bone formation.
Testosterone deficiency can result from disease or genetic disorders and is also frequently a complication of aging. Some of the sequelae of adult testosterone deficiency include a wide variety of symptoms including: loss of libido, erectile dysfunction, oligospermia or azoospermia, absence or regression of secondary sexual characteristics, progressive decrease in muscle mass, fatigue, depressed mood and increased risk of osteoporosis.
Several forms of testosterone therapy exist in the United States today. Recently, transdermal preparations have gained favor in the market. However, a scrotal testosterone patch results in supraphysiological levels of 5α-dihydrotestosterone (DHT) due to the high concentration of 5α-reductase in scrotal skin. Elevated DHT levels may have pernicious effects on the prostate over time. Nonscrotal systems are considered more convenient and most patients achieve average serum concentrations within the normal range and have normal levels of DHT. Oral testosterone therapy is not recommended because doses required for replacement therapy are associated with significant risk of hepatotoxicity.
b. Chronic Obstructive Pulmonary Disease
Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by a gradual and irreversible loss of lung function. COPD includes two related lung diseases: chronic bronchitis and emphysema. Chronic bronchitis is an inflammation and eventual scarring of the bronchial tubes. Emphysema is the loss of elasticity of lung tissue and destruction of alveoli-supporting structures and alveoli-feeding capillaries within the lungs. Persons with COPD have difficulty breathing due to smaller air passageways and partially destroyed alveoli. Additionally, the air passageways of persons with COPD become clogged with mucus. COPD represents the fourth leading cause of death in the United States, where 14 million people have been diagnosed with the disease. The most important risk factor for COPD is cigarette smoking.
Muscle wasting is prevalent in a large population of patients with COPD, and it is estimated that over 50% of COPD patients experience some loss of fat-free muscle. Loss of muscle mass adversely affects respiratory and peripheral muscle function, exercise capacity and health status and is a demonstrated predictor of mortality in COPD patients. Gain in muscle mass and strength, on the other hand, is associated with increased exercise capacity and survival. Muscle wasting in persons with COPD does not appear to result primarily from inadequate nutritional intake. Similar to cachexia, preferential loss of muscle tissue over fat, unresponsiveness to nutritional intervention and enhanced protein degradation are observed in persons with COPD.
On the basis of the chronicity of COPD and the elevated age of most COPD patients, it has been suggested that men with COPD may be at risk for hypogonadism. Importantly, low testosterone levels have been observed in patients with COPD, especially those undergoing glucocorticosteroid therapy and significant atrophy of Leydig cells has been observed in some COPD patients. However, it is currently unclear to what extent COPD contributes to the observed decreased testosterone levels.
Numerous studies suggest that hormones may play a role in weight loss and wasting. Androgen supplementation therapy, directed at curing dysfunction of the peripheral muscles in COPD patients, has been the subject of several controlled studies. Positive effects on fat-free mass and overall weight gain in COPD patients were reported in these studies. At least one study also reported improvements in muscle function and exercise capacity.
The aforementioned studies indicate the usefulness and efficacy of testosterone therapy in treating symptoms of COPD. However, high amounts of testosterone increase the risk of cardiovascular disease and benign prostate hyperplasia (BPH) and some forms of testosterone administration result in elevated levels of DHT. The association of high levels of serum DHT and BPH and the subsequent development of prostate cancer is a potential drawback to the use of testosterone gels or patches that enhance DHT.
c. Clomiphene
Clomiphene, which is an antiestrogen related to tamoxifen, has also been used to treat men with low testosterone levels. Clomiphene blocks the normal estrogen feedback on the hypothalamus and subsequent negative feedback on the pituitary. This leads to increases in luteinizing hormone (LH) and follicle stimulating hormone (FSH). In men, these increased levels of gonadotropins stimulate the Leydig cells of the testes and result in the production of higher testosterone levels.
Tenover et al., J. Clin. Endocrinol. Metab. 64:1103, (1987) and Tenover et al., J. Clin. Endocrinol. Metab. 64:1118 (1987) found increases in FSH, LH in both young and old men after treatment with clomiphene. They also found increases in free and total testosterone in men with young men showing significant increases.
Studies were also conducted to determine whether or not clomiphene could be used to improve fertility in men by improving semen quality. Homonnai et al. Fertil. and Steril 50:801 (1988) saw increases in sperm concentration and count but others have not. (See e.g., Sokel, et al., Fertil. and Steril. 49:865 (1988); Check, et al., Int. J. Fertil. 34:120 (1989); Purvis, et al., Int. J. Androl 21:109 (1989); and Breznik, Arch. Androl. 21:109 (1993).) One group saw a deterioration in the percentage of normal sperm with long-term treatment. Shamis, et al., Arch. Androl 21:109 (1991). A WHO study showed no changes in semen quality or fertility after 6 months of treatment. (Anonymous Androl. 15:299 (1992).) A meta-analysis seems to confirm that testosterone levels go up in men with poor quality sperm but not fertility. (Vanderkerckhove, et al., 2000).
Vandekerckhove, et al. (Cochrane Database Syst Rev 2000; (2):CD000151 (2000)) noted that ten studies involving 738 men have suggested that anti-estrogens appear to have a beneficial effect on endocrinal outcomes, i.e. testosterone, but there is not enough evidence to evaluate fertility effects. Nevertheless should clomiphene administration enhance testosterone levels then one could easily conclude that the drug should positively impact the side effects of testosterone deprivation as long as the testes still retain the ability to respond to gonadotropin stimulation.
Ernst et al., J. Pharmaceut. Sci. 65:148 (1976), have shown that clomiphene is a mixture of two geometric isomers which they refer to as cis, -Z-, clomiphene (cis-clomiphene or zuclomiphene) and trans-, E-, clomiphene, (trans-clomiphene or enclomiphene). According to Ernst, et al. trans-clomiphene HCI has a melting point of 149° C.-150.5° C., while cis-clomiphene HCI has a melting point of 156.5° C.-158° C. Ernst et al. have also noted that (the trans-isomer) is antiestrogenic (AE) while the cis-isomer is the more potent and more estrogenic form and has also been reported to have anti-estrogenic activity. The authors attribute the effect of the drug on ovulatory activity to both forms stating that the mixture is more effective than trans-clomiphene alone. The trans-isomer aids ovulation at the level of the hypothalamus. The estrogenic isomer cis-clomiphene contributes to enhanced ovulation elsewhere in the physiologic pathway leading to ovulation. The isomers are also reported to have different in vivo half-life. Furthermore the cis form has been reported to leave residual blood levels for in excess of one month following a single dose.
Clomiphene is currently approved as a mixture of both cis- and trans-isomers, the cis-isomer being present as about 30% to 50% (Merck Manual) for fertility enhancement in the anovulatory patient. Clomiphene improves ovulation by initiating a series of endocrine events culminating in a preovulatory gonadotropin surge and subsequent follicular rupture. The drug is recommended to be administered for 5 days at a dose of up to 100 mg daily. Clomiphene has also been associated with numerous side effects including: blurred vision, abdominal discomfort, gynecomastia, testicular tumors, vasomotor flushes, nausea, and headaches. Furthermore, other studies suggest that clomiphene possesses both genotoxic and tumor enhancement effects. The net outcome of these observations is that clomiphene in its current format, having between 30% and 50% of the cis isomer, would be unacceptable for chronic therapy.
There continues to be a need for methods of treating wasting and hypogonadism in patients with COPD which avoids the increased risk of cardiovascular disease and benign prostate hyperplasia (BPH) accompanying traditional testosterone supplementation regimens. The present invention addresses this need and provides novel compositions and methods for treating wasting and hypogonadism.